Symptomatic knee osteoarthritis (OA) is highly prevalent, disabling and costly. Pain related to knee OA is the principal driver of disability associated with this condition and attendant costs. Management of OA-related pain includes pharmacologic, non-pharmacologic, and surgical modalities. Clinicians and policy makers face critical questions related to effective pain management for knee OA: What is the impact of prolonged opioid use on patients' well-being? How do comorbidities affect medication choices and outcomes? Could novel analgesics offer sustainable pain relief at lower toxicity than currently available therapies? How do we scale up exercise and weight loss interventions to enable these programs to reach the millions of patients who might benefit from them? What efforts are needed to ensure adequate adherence to these interventions over time? At what age and level of functional status is it optimal to perform total knee replacement (TKR)? We propose to address these and related questions using a validated computer simulation model of knee OA natural history and treatment outcomes. We evaluate the health and economic effects of three major modalities of pain management in persons with knee OA: 1) the challenge posed by the increasing long-term use of opioids and by the chronic use of traditional pharmacologic agents in patients with comorbidities, along with the opportunities posed by novel analgesic agents; 2) the opportunities and costs associated with implementing, scaling up, and sustaining the benefits of exercise, weight loss, and behavioral interventions; and 3) the timing and sequencing of surgical options including unicompartmental and total knee replacement. We have assembled an expert multidisciplinary team of rheumatologists, orthopedists, epidemiologists, biostatisticians, decision analysts, and health economists to evaluate the Clinical impact and cost-effectiveness of pain management in knee OA. This proposal has the following three specific aims: 1. To examine the long-term clinical impact and cost-effectiveness of pharmacologic analgesic strategies for knee OA that employ approved and investigational agents. 2. To examine the clinical and economic consequences of strategies related to the delivery of non- pharmacologic management in persons affected by knee OA. 3. To evaluate the long-term clinical impact and cost-effectiveness of alternative knee replacement strategies in persons with knee OA. This project will guide clinicians and policy makers in their efforts to reduce pain and disability and improve quality of life for people with knee OA.